Title

Rhodium-Catalyzed C–H Activation for the Synthesis, Elaboration, and Application of N-Heterocyclic Compounds

Date of Award

Fall 10-1-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Ellman, Jonathan

Abstract

Nitrogen heterocycles are present in almost two-thirds of U.S. FDA approved pharmaceuticals, garnering interest in efficient ways to construct and functionalize these valuable scaffolds. The first two chapters of this dissertation will discuss the development of transition metal-catalyzed C–H activation methodology for the branched alkylation of benzimidazoles and the synthesis of [1,3,5]triazinones, respectively. The third chapter provides a review of N-heterocyclesynthesis from a 1,2-dihydropyridine intermediate, and the final chapter depicts the application of one of these methods in a new approach for small molecule ligand discovery via virtual library-guided synthesis. Chapter 1 describes a Rh(I)/bisphosphine/K3PO4 catalytic system allowing for the first time the selective branched C–H alkylation of benzimidazoles with Michael acceptors. Branched alkylation with N,N-dimethyl acrylamide was successfully applied to the alkylation of a broad range of benzimidazoles incorporating a variety of N-substituents and with both electron-rich and electron-poor functionality displayed at different sites of the arene. Moreover, the introduction of a quaternary carbon was achieved by alkylation with ethyl methacrylate. The method was also shown to be applicable to the C2-selective branched alkylation of azabenzimidazoles. Chapter 2 describes a Rh(III)-catalyzed synthesis of bicyclic [1,3,5]triazinones from a diverse array of imines coupled with ethyl (pivaloyloxy)carbamate. The preparation of [5,6]- and [6,6]-bicyclic heterocycles substituted with aryl, alkyl, and alkoxy groups demonstrated a broad reaction scope. The efficiency of this approach was further enhanced with the development of a three-component variant featuring in situ imine formation. X-ray crystallographic characterization of a rhodacycle formed by imidoyl C–H activation provides support for the proposed mechanism. Chapter 3 gives a review of the utility of 1,2-dihydropyridines as intermediates towards many classes of nitrogen heterocycles. Our lab has shown that 1,2-dihydropyridines can be synthesized via a Rh-catalyzed C–H bond alkenylation/electrocyclization cascade from readily available α,β-unsaturated imines and alkynes. This chapter details the variety of transformations that have been developed using this intermediate to form medicinally-relevant heterocyclicframeworks, such as six-membered tetrahydropyridines and piperidines as well as bicyclic isoquinuclidines, tropanes, and indolizidines. Chapter 4 details an investigation using structure-based docking with a virtual library of tetrahydropyridines (THPs) to identify unique agonists for the serotonin 5-HT2A receptor (5-HT2AR). Based around combinations of three inputs, which in a one pot C–H alkenylation, electrocyclization, and reduction sequence provide a tetrahydropyridine framework, a virtual library of 75 million tetrahydropyridines was created. Docking of this library against a model of 5-HT2AR prioritizedcompounds for initial synthesis. Optimization of four lead compounds using a cycle of design, synthesis, and testing for binding and function revealed two potent 5-HT2AR agonists with unusual biological activity that differs from psychedelic 5-HT2AR agonists.

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